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Activation of c-Jun NH2-terminal kinase (JNK) signaling pathway is essential for the stimulation of hepatitis C virus (HCV) non-structural protein 3 (NS3)-mediated cell growth

Virology. 2005 Mar 15;333(2):324-36. doi: 10.1016/j.virol.2005.01.008.

Abstract

Hepatitis C virus (HCV) non-structural protein 3 (NS3) has been shown to affect cellular functions and is thought to contribute to the development of HCV-related hepatocarcinogenesis. In this study, we delineated part of the mechanisms whereby NS3 protein stimulates cell growth in liver (HepG2) and non-liver (HeLa) cells. The expression of NS3 protein enhanced cell growth, c-jun NH(2)-terminal kinase (JNK) activation, DNA binding activities of the transcription factors AP-1 and ATF-2, and c-jun expression, but not the activation of extracellular signal-regulated kinase (ERK) or p38(MAPK). Whereas co-expression of NS3 with its cofactor NS4A inhibited NS3-mediated cell growth without to influence NS3-mediated JNK activation, or to affect the basal activities of ERK or p38(MAPK). Pre-treatment of NS3 protein-expressing cells with JNK inhibitor, SP600125, abolished activation of AP-1 and ATF-2 and inhibited c-jun expression and induced cell growth, suggesting that JNK activation is essential for the stimulation of NS3-mediated cell growth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 2
  • Anthracenes / pharmacology
  • Base Sequence
  • Cell Division / drug effects
  • Cell Line
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • DNA, Viral / genetics
  • Enzyme Inhibitors / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression / drug effects
  • Genes, Viral / drug effects
  • HeLa Cells
  • Hepacivirus / drug effects
  • Hepacivirus / genetics
  • Hepacivirus / pathogenicity*
  • Humans
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • MAP Kinase Signaling System / drug effects
  • Tetracycline / pharmacology
  • Transcription Factor AP-1 / metabolism
  • Transcription Factors / metabolism
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / physiology*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • ATF2 protein, human
  • Activating Transcription Factor 2
  • Anthracenes
  • Cyclic AMP Response Element-Binding Protein
  • DNA, Viral
  • Enzyme Inhibitors
  • NS3 protein, hepatitis C virus
  • NS4 protein, hepatitis C virus
  • Transcription Factor AP-1
  • Transcription Factors
  • Viral Nonstructural Proteins
  • pyrazolanthrone
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Tetracycline